Management of Oligoprogressive Castration Resistant Prostate Cancer (PCS X)

Inclusion Criteria (Part 1): * Histologically confirmed adenocarcinoma of the prostate without neuroendocrine differentiation or small cell features; * M0CRPC at study entry defined as follows: 1. Ongoing androgen deprivation therapy with a LHRH agonist or bilateral orchiectomy (i.e., surgical or medical castration); 2. Serum testosterone level ≤ 1.7 nmol/L (50 ng/dL) at the Screening visit; 3. PSA progression defined by a minimum of two subsequent rising PSA levels with an interval of ≥ 1 week between each determination. Patients who received an anti-androgen must have progression after withdrawal (≥ 4 weeks since last flutamide or ≥ 6 weeks since last bicalutamide or nilutamide). The PSA value at the Screening visit should be ≥ 2 μg/L (2 ng/mL) 4. PSA doubling time of 10 months or less, 5. M0 assessed by conventional imaging (CT/MRI + bone scan). NOTE: If darolutamide started prior to study entry, evidence of inclusion criteria 1-5 listed above prior to start of darolutamide must be submitted to determine study eligibility * Prior cytotoxic chemotherapy for prostate cancer in adjuvant setting post radical therapy is allowed; * Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 or Karnofsky performance status of \> 80% or higher; * Estimated life expectancy of ≥ 6 months; * Ability to swallow the study drug whole and comply with study. * Patients should not have been previously exposed to other ARATs (Abiraterone, Enzalutamide, Apalutamide) Inclusion Criteria (Part 2): * ≤ 5 metastatic sites (on conventional imaging); * ≤ 4 tumors within any given organ system, excluding brain (e.g. up to 4 bone metastases, or 4 lung metastases); * All sites of disease must be amenable to SBRT with no history of the metastases being irradiated (radiation exposure prior to the development of the metastases is permitted as long as the radiation exposure was not intended for the metastases. For example, if there is prior pelvic radiation to the prostate and a subsequent iliac metastasis develops within the previously irradiated pelvic radiation field, then the iliac metastasis would be eligible per the institution policy and practice); * In the case of a suspicious lesion in an unusual location such as lung or thoracic lymph nodes (without other abdominal lymph nodes), a confirmatory imaging or biopsy is strongly recommended; Exclusion Criteria (Part 1): * Severe concurrent disease, infection, or co-morbidity that, in the judgment of the Investigator, would make the patient inappropriate for enrollment; * Presence of distant metastasis, including previously treated (clinical stage M1) is exclusive, however isolated pelvic nodal disease below the iliac bifurcation (clinical stage N1) is not an exclusion criteria. * History of another malignancy within the previous 5 years other than curatively treated non-melanoma skin cancer; * Absolute neutrophil count \< 1,500/μL, platelet count \< 100,000/μL, or hemoglobin \< 5.6 mmol/L (9 g/dL) at the Screening visit (NOTE: patients may not have received any growth factors within 7 days or blood transfusions within 28 days of the hematologic laboratory values obtained at the Screening visit); * Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) \> 2.5 times the upper limit of normal and total bilirubin \> 1.5 times the upper limit of normal at the Screening visit; * Creatinine \> 2 times the upper limit of normal at the Screening visit; * Clinically significant cardiovascular disease including: 1. Stroke or myocardial infarction within 6 months; 2. Uncontrolled angina within 6 months; 3. Coronary/peripheral artery bypass graft within 6 months; 4. Congestive heart failure New York Heart Association (NYHA) class 3 or 4, or patients with history of congestive heart failure NYHA class 3 or 4 in the past, unless a screening echocardiogram or multi-gated acquisition scan performed within three months results in a left ventricular ejection fraction that is ≥ 45%; 5. History of Mobitz II second degree or third degree heart block without a permanent pacemaker in place; 6. Uncontrolled hypertension as indicated by a resting systolic BP ≥160 mmHg or diastolic BP ≥100 mmHg at screening. Patients may be re-screened after adjustments of antihypertensive medications; 7. Bradycardia as indicated by a heart rate of \< 50 beats per minute on the Screening ECG; * Gastrointestinal disorder or procedure which expects to interfere significantly with absorption (e.g., gastrectomy, active peptic ulcer disease within last 3 months); * Major surgery within 4 weeks of enrollment (Day 1 Visit); * Active viral hepatitis, active human immunodeficiency virus (HIV) or chronic liver disease * Use of opiate analgesics (eg. morphine, fentanyl, etc.) for pain from prostate cancer within 4 weeks of enrollment (Day 1 visit). This does not apply to non-morphine drugs like codeine; * Radiation therapy for treatment of the primary tumor within 3 weeks of enrollment (Day 1 visit); * Radiation or radionuclide therapy for treatment of metastasis; * Primary disease not treated; * Hormone naïve prostate cancer patients; * Treatment with estrogens or AR inhibitors (bicalutamide, flutamide, nilutamide, cyproterone acetate) within 4 weeks of enrollment (Day 1 visit); * Treatment with systemic biologic therapy for prostate cancer (other than approved bone targeted agents and GnRH-analogue therapy) or other agents with anti-tumour activity within 4 weeks of enrollment (Day 1 visit); * Prior use of an investigational agent that blocks androgen synthesis (e.g., abiraterone acetate, enzalutamide, Apalutamide, TAK-700, TAK-683, TAK-448) or targets the androgen receptor (e.g., BMS 641988) on clinical trials; * Known or suspected contraindications or hypersensitivity to darolutamide or GnRH agonists or any of the components of the formulations; * Use of an investigational agent within 4 weeks of enrollment (Day 1 visit); * Use of herbal products that may have hormonal anti-prostate cancer activity and/or are known to decrease PSA levels (e.g., saw palmetto) or systemic corticosteroids greater than the equivalent of 10 mg of prednisone per day within four weeks of enrollment (Day 1 visit); * Any condition or reason that, in the opinion of the Investigator, interferes with the ability of the patient to participate in the trial, which places the patient at undue risk, or complicates the interpretation of safety data; * Unable to swallow study medications and comply with study requirements Exclusion criteria (Part 2): * Known or suspected brain metastasis or active leptomeningeal disease; * \> 5 metastasis; * More than 4 metastasis in the same organ; * Patients considered for SBRT in previous history of radiation therapy to the same area.